The inability to eliminate urine and/or feces is a life-threatening condition. The current standard of care for urinary voiding dysfunction requires passage of a clean catheter through the urethra and further into the urinary bladder to facilitate urine flow through the catheter externally. The current standard of care for fecal dysfunction includes digital extraction of feces from the rectum in combination with a diet conducive to stool passage. Some patients receive large volume (1 L) warm water enemas that can require waiting for 30 minutes to an hour while the water and fecal contents are expelled.
Patients with voiding dysfunction may also experience episodes of incontinence, whereby the large volume of urine and/or feces in the bladder and/or bowel are subject to acute increases in intraluminal pressure that force urine and/or feces past the urethral and/or anal sphincters. While accidental voiding has occurred, the void may be incomplete, and the patient remains at risk for urinary tract infections and/or bowel problems.
Voiding dysfunction is extremely prevalent in patients with spinal cord injury, spina bifida, multiple sclerosis, and other conditions involving spinal cord pathology. Voiding dysfunction is also prevalent in subjects with diabetic cystopathy and gastroenteropathy. Voiding dysfunction is also seen in various elderly subjects and is prevalent among the institutionalized.
Existing therapies for urinary voiding dysfunction include either clean intermittent or indwelling catheterization which can result in catheter associated urinary tract infections (CAUTI). CAUTI account for more than 15% of infections reported by acute care hospitals and can lead to complications such as cystitis, pyelonephritis, gram-negative bacteremia, prostatitis, epididymitis, and orchitis in males and, less commonly, endocarditis, vertebral osteomyelitis, septic arthritis, endophthalmitis, and meningitis in all patients. Complications associated with CAUTI cause discomfort to the patient, prolong hospital stay, and increase cost and mortality. Each year, more than 13,000 deaths are associated with UTIs. In addition, persons with SCI (and other CNS damage) often lack the physical ability to catheterize themselves.
Cholinergic agonists such as bethanechol (a muscarinic receptor agonist) and distigmine (an acetylcholinesterase inhibitor) have been used as therapy. However, the efficacy of these compounds is limited and tolerability is low due to severe side effects such as sweating, spasticity, bradycardia, convulsions, hypotension, bronchial constriction (Taylor and Kuchel 2006). Alternative methods have been developed to empty the bladder by preventing the sphincter from closing the urethra, but most of them, including sphincterotomy, sphincter paralysis, and urethral stenting, leave the person incontinent and lead to further complications.
Lower urinary tract disorders including underactive bladder and incontinence greatly affect the quality of life of patients. Voiding dysfunction associated with the inability to completely void the bladder of urine during micturition is a condition affecting the elderly, diabetic, neurogenic (spinal cord injury, spina bifida, multiple sclerosis, stroke patients, traumatic brain injury, Parkinson's, Alzheimer's, ALS), and other patient populations. The condition can arise from impaired contractility of the bladder smooth muscle of myogenic nature, e.g. in the elderly; impaired relaxation of the urethral smooth muscle, e.g. in the elderly; damage of the peripheral nerves (afferents and/or efferents) e.g. in diabetic neuropathy; impaired neuronal control due to injury of the spinal cord or brain, e.g. in spinal cord injury, multiple sclerosis, stroke patients, traumatic brain injury, Parkinson's, Alzheimer's, and other conditions and disorders. This condition can lead to elevated post-void residual urine volumes and symptoms of frequency, nocturia, incontinence, and urinary tract infections.
The International Continence Society refers to the condition of detrusor under activity, defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a usual time span. It is characterized by the loss of usual sensation of the bladder filling and failure of the detrusor muscle to contract as forcefully as it should, resulting in incomplete bladder emptying. This condition has also been referred to as a hypotonic or flaccid bladder or detrusor hypoactivity. Underactive Bladder Syndrome is a chronic, complex and debilitating disease which affects the urinary bladder with serious consequences. Detrusor underactivity has been found in nearly two-thirds of the incontinent institutionalized elderly. However, the incidence and prevalence of a condition is highly dependent on both definition and available diagnostic tests (Taylor and Kuchel 2006).
Spinal cord injury is the most common injury that profoundly affects voiding and usually results from traffic accidents, sports injuries, but also from infections, vascular disorders, cancers, congenital malformations, polio, tuberculosis, etc. It is estimated that the annual incidence of spinal cord injury (SCI), not including those who die at the scene of the accident, is approximately 40 cases per million population in the U. S. or approximately 12,000 new cases each year. The number of people in the United States who are alive in 2012 who have SCI has been estimated to be approximately 270,000 persons, with a range of 236,000 to 327,000 persons.
For a person with SCI, the direct medical costs associated with urinary tract dysfunction may exceed $8,000 each year, making up a substantial component of the estimated $31,000 to $75,000 annual health care and living expenses of individuals with spinal injury. Furthermore, the loss of control of urinary function alters social relationships and can be personally demoralizing, and it can lead to depression, anger, poor self-image, embarrassment, frustration and can prevent persons from achieving their personal goals.
Following spinal cord injury, the bladder is usually affected in one of two ways. The first is a condition called “spastic” or “reflex” bladder, in which the bladder fills with urine and a reflex automatically triggers the bladder to empty. This usually occurs when the injury is above the T12 level. Individuals with spastic bladder are unable to determine when, or if, the bladder will empty. The second is “flaccid” or “non-reflex” bladder, in which the reflexes of the bladder muscles are absent or slowed. This usually occurs when the injury is below the T12/L1 level. Individuals with flaccid bladder may experience over-distended or stretched bladders and “reflux” of urine through the ureters into the kidneys. Treatment options for these disorders usually include intermittent catheterization, indwelling catheterization, or condom catheterization, but these methods are invasive and frequently inconvenient.
Urinary sphincter muscles may also be affected by spinal cord injuries, resulting in a condition known as “dyssynergia.” Dyssynergia involves an inability of urinary sphincter muscles to relax when the bladder contracts, including active contraction in response to bladder contraction, which prevents urine from flowing through the urethra and results in the incomplete emptying of the bladder and “reflux” of urine into the kidneys. Traditional treatments for dyssynergia include medications that have been somewhat inconsistent in their efficacy or surgery.
Injury to spinal cord and/or brain can lead to inability to voluntarily defecate. Currently patients use manual extraction of feces, or in some cases use large volume (1 L) warm water enemas that require sitting on the toilet for 30 minutes to an hour while the water and fecal contents are expelled. In some cases, an irritative “stimulant laxative” is administered intra-rectally, although effects may last hours longer than necessary and cannot be administered on a regular basis. These methods are either performed by the patient, if able to perform them, or by the caregiver. They can be degrading to the self-esteem of patients and can be personally demoralizing, altering social relationships, leading to depression, anger, poor self-image, embarrassment, frustration, etc.
Fecal incontinence is defined as accidental passing of solid or liquid stool or mucus from the rectum. Fecal incontinence includes the inability to hold a bowel movement until reaching a toilet as well as passing stool into one's underwear without being aware of it happening. Fecal incontinence can be upsetting and humiliating. The condition affects ˜18 million people in the US.
Constipation is one of the most common forms of gastrointestinal hypomotility disorders. Constipation is one of the most common gastrointestinal complaints in the United States. More than 4 million Americans have frequent constipation, accounting for 2.5 million physician visits a year. Self-treatment of constipation with over-the-counter (OTC) laxatives is by far the most common aid. Around $725 million is spent on laxative products each year in America.
Constipation is common in a number of gastrointestinal tract disorders including but not limited to irritable bowel syndrome, celiac disease or gluten-sensitive enteropathy, megacolon associated with hypothyroidism, pseudo-obstruction of the gastrointestinal tract, colitis, hypomotility of the colon associated with diabetes mellitus, adult onset Hirschsprung's disease, neurological disorders, myopathic disorders, spinal cord injury, Parkinson's disease, jejunal-ileal bypass with secondary megacolon, cancer chemotherapy, critical illness including severe burns and other major stresses, with syndromes of depression, the post-operative state, and other pathological conditions.
Present treatments include: over-the-counter (OTC) laxatives, AMITIZA (lubiprostone which is a chloride channel activator; approved for irritable bowel syndrome with constipation or IBS-C), LINZESS (linaclotide; a guanylatecyclase-C agonist; approved for the treatment of IBS-C and chronic idiopatic cystitis, CIC). However, none of these available medications produce colon contraction and expulsion of feces, rather they increase the fluid in the intestines.
Because existing therapies and treatments for voiding dysfunction are associated with limitations as described above, new therapies and treatments are therefore desirable. The presently disclosed subject matter provides such new therapies and treatments to address these limitations.